The role of p53 gene family in reproduction

Abstract

The p53 family of genes (p53, p63, and p73) is conserved over evolutionary time scales. Although the functions of p53 gene and its protein as a tumor suppressor have been firmly established, the earliest functions for the p53 ancestral genes in worms and flies are to ensure germ-line genomic integrity and the fidelity of the developmental process. In vertebrates, the p53 family of genes retains those functions in germ-line genomic integrity but have added important functions in regulation of reproduction. Loss of the p53, p63, or p73 genes in female mice leads to a significant decrease of fertility. The p53 gene product regulates maternal reproduction at the implantation stage of the embryo. p63 and p73 play important roles in monitoring the genomic quality of oocytes. The p53 pathway appears to play a similar role in human fertility. In humans, certain alleles containing a functional single-nucleotide polymorphism (SNP) in the p53 pathway are under positive evolutionary selection. Selected alleles of these SNPs in the p53 pathway are associated with decreased fertility. This important function of the p53 pathway in reproduction provides a plausible explanation for the evolution of p53 as a tumor suppressor gene and the positive selection of some alleles in the p53 gene and its pathway. These observations provide a good possible example of antagonistic pleiotrophy for fertility, tumor suppression, and longevity.

Figure 1.

p53 regulates maternal reproduction through LIF in mice. At the implantation stage in mice (day 4 of pregnancy), estrogen (E2) and p53 induce uterine LIF expression at sufficient levels, which is crucial for uterine decidualization and implantation of blastocysts (A). p53 loss decreases uterine LIF levels at the implantation stage, which leads to impaired function in uterine decidualization and implantation (B). Administration of exogenous LIF to p53−/− mice at day 4 of pregnancy could restore reproduction by improving implantation (C).

Figure 2.

SNPs in the p53 pathway associated with human fertility. Naturally occurring polymorphisms in the p53 pathway listed in the diagram, which modify the function of the p53 pathway, could have an impact on human fertility.